GGA1-mediated endocytic traffic of LR11/SorLA alters APP intracellular distribution and amyloid-? production.

ABSTRACT: Proteolytic processing of the amyloid-? precursor protein (APP) and generation of amyloid-? peptide (A?) are key events in Alzheimer's disease (AD) pathogenesis. Cell biological and genetic evidence has implicated the low-density lipoprotein and sorting receptor LR11/SorLA in AD through mechanisms related to APP and A? production. Defining the cellular pathway(s) by which LR11 modulates A? production is critical to understanding how changes in LR11 expression affect the development of A? pathology in AD progression. We report that the LR11 ectodomain is required for LR11-mediated reduction of A? and that mutagenesis of the LR11 Golgi-localizing, ?-adaptin ear homology domain, ADP-ribosylation factor (GGA)-binding motif affects the endosomal distribution of LR11, as well as LR11's effects on APP traffic and A? production. Targeted small interfering RNA (siRNA) knockdown studies of GGA1, GGA2, and GGA3 indicate a surprising degree of specificity toward GGA1, suggesting that GGA1 is a candidate regulator of LR11 traffic. Additional siRNA knockdown experiments reveal that GGA1 is necessary for both LR11 and ?-site APP-cleaving enzyme-1 (BACE1) modulation of APP processing to A?. Mutagenesis of BACE1 serine 498 to alanine enhances BACE1 targeting to LR11-positive compartments and nullifies LR11-mediated reduction of A?. On basis of these results, we propose that GGA1 facilitates LR11 endocytic traffic and that LR11 modulates A? levels by promoting APP traffic to the endocytic recycling compartment.

SUBMITTER: Herskowitz JH 

PROVIDER: S-EPMC3395654 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature